The objective of the proposed project is to determine how the mechanisms of fetal cardiac growth are altered by recovery from an extended period of increased cardiovascular volume or pressure load. The fetal heart very sensitively adjusts to alterations in hemodynamic loading conditions by modifying its normal growth patterns. During normal growth, the fetus undergoes extensive cardiomyocyte proliferation (prior to terminal differentiation) as well as cardiomyocyte enlargement. The possibility of fetal therapies raises the question of how the fetal heart recovers after correction of altered hemodynamic loading conditions. Increased volume load and increased pressure load both increase the ratio of the heart to body weight, but recovery from these conditions may be different. Aim 1: When the fetal heart/body weight normalizes following a transient period of accelerated cardiomyocyte proliferation, the number of myocytes within the myocardium is normal. This hypothesis is supported by our finding that myocytes are not larger in hypertrophied hearts of anemic fetuses. Following recovery, the fetal heart will therefore contain a normal number of myocytes. Aim 2: When the fetal heart/body weight normalizes following a transient period of accelerated cardiomyocyte enlargement, the number of myocytes within the myocardium is reduced. This hypothesis is supported by our finding that hypertension induces cardiomyocyte enlargement. Following recovery, the fetal heart will therefore contain a fewer number of myocytes. Aim 3: Apoptosis and signaling pathways associated with apoptosis are activated in the fetal heart in the recovery period following a pressure load, but not a volume load. Volume load (due to anemia) does not increase arterial pressures, therefore correction of volume load will not change systolic wall stress and apoptosis will not be strongly stimulated. In contrast, during hypertension the fetal heart will normalize wall stress by reducing the ventricular radius of curvature and increasing wall thickness. Upon unloading, ventricular wall stress will fall and induce apoptosis. Fetuses have a remarkable capacity for growth and adaptation. Many babies tolerate congenital cardiovascular diseases better before they are born. We are trying to learn how the hearts of fetuses recover from such conditions. This will help us know when fetal therapies will do the most good. [unreadable] [unreadable] [unreadable]